Antigen-specific tolerance in immunotherapy of Th2-associated allergic diseases

Abstract

Allergic diseases are an increasing health concern, particularly in the developed world. The standard clinical approach to treatment of allergic disease focuses on allergen avoidance and symptom control but does little to address the underlying Th2 bias of disease. Specific immunotherapy (SIT) consisting of controlled administration of allergen, however, has been demonstrated to successfully induce desensitization and tolerance in an antigen-specific manner for a variety of Th2-mediated diseases. This review focuses on the mechanisms by which current SIT approaches induce tolerance as well as discussing attempts to modify the safety and efficacy of SIT. These refinements focus on three major aspects of SIT: the route of antigen administration, modification of the antigen to remove allergenic epitopes and reduce adverse events and choice of adjuvant used to induce tolerance and/or immune deviation from Th2 to Th1 and regulatory T-cell (Treg) phenotypes. Synthesis of these recent developments in SIT provides considerable promise for more robust therapies with improved safety profiles to improve resolution of allergic disease and its associated costs.

FIGURE 1

Mechanisms of SIT for allergic diseases. Antigen in the presence or absence of adjuvant or carrier is processed by APCs and presented to T cells. A. In the absence of positive costimulation and/or the presence of negative costimulation via PD-L1/2, Th2 effector cells are driven towards clonal anergy or apoptosis. Additionally, SIT leads to the induction and expansion of Treg, Tr1 and Th1 cells by APCs producing IL-10, TGF-β and IL-12, respectively. B. Tregs suppress effector cells such as mast cells, basophils and eosinophils both directly and indirectly through suppression of Th2 cells and induction of IgG4-producing B cells. C. Th1 cells produce IFN-γ^, which inhibits Th2 cell differentiation and induces B cells to produce IgG that competes with pathogenic IgE for antigen.